The central goal of the proposed research is to determine mechanisms by which viral infections lead to loss of oral tolerance and induce celiac disease (CD). Viral infections are increasingly recognized as contributing factors in the pathogenesis of complex inflammatory diseases. However, little is known about the biological features that enable a virus to provoke development of inflammatory disorders. CD is a complex T cell- mediated intestinal disorder with an autoimmune component characterized by an inflammatory anti-gluten immune response that occurs exclusively in gluten-exposed persons with HLA DQ2 or DQ8 alleles. Gaps in knowledge preclude precise identification of at-risk individuals and development of new ways to prevent and treat CD. Approximately 45% of the U.S. population expresses DQ2 or DQ8 molecules, yet only 1% of the population develops the disease. This observation indicates that additional environmental factors contribute to disease induction. Although a common feature of CD is loss of oral tolerance (LOT) to gluten, we have new evidence that CD is a heterogeneous disorder consisting of two main types. Type A CD is mediated by IL-15, whereas Type B CD is mediated by viral infections and elaboration of type-1 interferons. Reoviruses are particularly attractive models for studies of CD-potentiating viral infections. These viruses are human dsRNA viruses that belong to the Reoviridae, which are associated with an increased CD incidence. Reoviruses infect the murine intestine and can be genetically manipulated to identify viral determinants of autoimmune host responses. The central hypothesis of this proposal is that responses to viral infections constitute an alternative pathway to IL-15 signaling or effector responses that leads to CD by dysregulating immune responses to oral antigen (Ag). This hypothesis will be tested in two well-integrated specific aims. In Specific Aim 1, we will identify viral determinants that shape the virus-host interaction implicated in LOT by using reassortant viruses generated from two well-characterized reovirus strains that differ in LOT capacity. In Specific Aim 2, we will establish evidence for virus-induce CD by characterizing the capacity of reovirus infection to induce potential CD in HLA-DQ8 tg mice as well as establishing evidence for a Type A and Type B CD while defining transcriptional signatures for virus-induced CD. Insights gained from these studies will enable identification of candidate pathways for virus-induced Type B CD. This project brings together three internationally recognized PIs with complementary expertise in CD, mucosal immunology, virology, and systems biology. Knowledge gained through these efforts will enhance an understanding of how viral infections lead to development of complex disorders. Furthermore, by dissecting pathways involved in CD pathology triggered by different stimuli, we will personalize CD and promote prevention and treatment based on specific CD mechanisms.